Obsessive-compulsive disorder (OCD) affects 1-2% of children, runs a chronic course without treatment, and is associated with considerable functional impairment and poor quality of life. Although most patients with OCD respond to cognitive-behavioral therapy (CBT) or pharmacotherapy with a serotonin reuptake inhibitor (SRI), a substantial number of youth remain symptomatic after receiving these therapies. Pharmacological interventions with SRIs are only moderately efficacious, rarely produce remission, may be accompanied by side effects, and may not be an acceptable intervention to some parents. Medication augmentation strategies such as atypical antipsychotics are often used in children with partial response but have concerning metabolic effects and no systematic supporting efficacy or safety data. Although CBT is the gold standard treatment for pediatric OCD, not all patients benefit and the availability of skilled therapists is quite limited. Thus, there is a critical need for interventions to improve treatment outcome in pediatric OCD. The primary mechanism in CBT is repeated and prolonged exposure to feared situations while abstaining from OCD rituals. This treatment is based on animal models of extinction of conditioned fears. Basic research on the neural circuitry underlying fear extinction led to the examination of d-cycloserine (DCS), a partial agonist at the NMDA receptor in the amygdala, as an agent capable of enhancing extinction learning. Following successful validation of this strategy in animals, six trials in adult humans - and our NIH-funded pilot study in youth with OCD - provide support for DCS dosing as facilitating extinction learning that occurs during exposure-based psychotherapy. However, experts and agencies responsible for regulating drug indications in the US, including the FDA, recognize that safety and efficacy findings in adults should not be routinely extrapolated to children. The present study furthers our pilot work on DCS to augment the effects of CBT in children with OCD. We propose a double-blind randomized controlled trial, conducted at two sites, to examine the relative benefit of 10 psychotherapy sessions of which sessions 4-10 will be augmented with weight-adjusted doses of DCS (25/50mg) compared to CBT augmented with placebo. 150 youth (ages 7-17) with OCD will be randomly and evenly assigned to one of the two treatment conditions. The primary outcome will be change in OCD symptom severity assessed by independent evaluators. The study recruitment sites are the University of South Florida (USF) and Massachusetts General Hospital/Harvard Medical School (MGH). USF will provide data management services while MGH will provide pharmacokinetic assays. Our study extends the first report of DCS augmentation in youth with anxiety disorder/OCD by conclusively investigating an innovative research approach that manipulates glutamatergic pathways to mediate improved outcomes of exposure-based psychotherapy based upon a translational model of the neurobiology of OCD. This study will yield clinically important data, which could ultimately improve the treatment of youth with OCD and reduce exposure to potentially harmful medications. PUBLIC HEALTH RELEVANCE: We are proposing a randomized double-blind placebo-controlled study to assess the efficacy of d-cycloserine augmentation of cognitive-behavioral therapy for the treatment of pediatric obsessive compulsive disorder. This study represents an innovative approach in translating bench research findings into clinical research and testing a new approach for augmenting an effective psychotherapy with a safe non-psychotropic medication.